Background Gastrointestinal stromal tumors (GIST) are very rare in the pediatric population, affecting less than 100 children yearly. The rarity of this tumor has precluded the ability to perform systematic clinical and research studies, and treatment regimens have varied widely from one institution to another. The lack of patients has also led to the reliance of case reports as the extent of the published literature. In order to mitigate these deficiencies, the Pediatric Oncology Branch of the National Cancer Institute and the Pediatric Endocrinology Unit of the National Institute of Child Health &Human Development have collaborated to initiate the NIH Pediatric and wildtype GIST Clinic. This is a bi-annual clinic that brings children and young adult GIST patients together with some of the leading clinicians and researchers in the field of GIST. In 2008, we held the inaugural NIH Pediatric and wildtype GIST Clinic. Results from 2011 In 2011, we completed the sixth and seventh NIH Pediatric and wildtype GIST Clinics and 80 patients have participated in total. We have gained value data relating to clinical parameters and have performed numerous research studies. We identified germline mutations in subunits of the succinate dehydrogenase gene in 15% of wildtype GIST patients and demonstrated functional loss of both copies of these subunits. Concurrently, we have also shown loss of SDHB, regardless of germline mutation status, in all pediatric patients and also in 70% of adults with wildtype GIST by western blot analysis, suggesting that disruption of genes in this pathway plays an important role in this disorder. These results were published in the journal Proceedings of the National Academy of Sciences USA. We also collaborated with members of many laboratories and found very interesting novel findings. Activating BRAF mutations occur in 15% of patients with SDHB-positive GIST. Manuscript in preparation. SDHB-negative GIST is associated with a divergent methylation pattern. Collaboration with Dr. Paul Meltzer. Manuscript submitted. The role of miRNAs in the pathogenesis of pediatric GIST. Collaboration with Dr. Maureen OSullivan. Poster presented and published at the 2011 American Association of Cancer Research Annual Conference. Plans for 2012 In 2012, we have the following specific objectives for the NIH Pediatric and wildtype GIST Clinic. 1 Continue with the eighth and ninth clinics to allow more patients to undergo evaluation 2 Sequence genes in the SDH pathway of SDHB-deficient GIST to determine if they harbor aberrations 3 Perform germline sequencing of SDHB-positive germline samples to identify putative pathogenic genes 4 Continue to collect fresh tissue for establishment of cell lines and murine xenografts 5 Begin next generation sequencing on flash frozen tumor and normal blood samples Significance and Goals The successful completion of the above objectives will allow us to continue to build on the wealth of knowledge about the natural history of pediatric GIST. Further examination of genes that are thought to play a role in this disease will allow us to continue to translate our research findings into the clinic by placing patients into a suitable clinical trial. The success of this clinic has allowed us to perform the preparatory steps for bold and innovative research studies, including global assessment of genetic stability, examination of the importance of miRNA in this disorder, and next generation sequencing. Our hope is that the successful completion of the above research objectives will propel the design of innovative national protocols for the treatment of patients with GIST. We believe that our clinic has proven to be an excellent model of how to study rare diseases. Papers and Presentations in 2011 Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, Dahia PLM, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL, NIH Pediatric and wild-type GIST Clinic, OSullivan M, de Krijger RR, Dinjens WNM, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 2011;108:314-318. PMID 21173220. Kelly L, Bryan K, Kim SY, Debiec-Rychter M, OSullivan MJ. An investigation into the role of miRNAs in the pathogenesis of pediatric gastrointestinal stromal tumor. Proc Am Assoc Cancer Res 2011;52supp:#169.